The compound, which is the subject of the present invention (Compound I, trans-1-((1R,3S)-6-chloro-3-phenylindan-1-yl)-3,3-dimethylpiperazine) has the general formula (I).

Compound I and salts thereof, including a fumarate salt and a maleate salt, are described in PCT/DK04/000546 (WO05/016901).
As described in PCT/DK04/000546 the inventors have found that Compound I displays high affinity for dopamine (DA) D1 receptors, DA D2 receptors and for alfa1 adrenoceptors. Furthermore, Compound I was found to be an antagonist at dopamine D1 and D2 receptors, and at serotonin 5-HT2a receptors. As further described in PCT/DK04/000546, Compound I is a relatively weak inhibitor of CYP2D6 (i.e. reduced potential for drug to drug interaction) and has a relatively low effect on the QT interval in a rabbit model (i.e. reduced potential for introducing drug-induced QT interval prolongation and appearance of fatal cardiac arrhythmias, torsade de pointes (TdP), in humans). Additionally, the 5-HT2 antagonistic activity of Compound I suggests that Compound I may have a relatively low risk of extrapyramidal side effects.
The properties outlined above, e.g. binding assays (including alfa1, DA D1 or D2 receptors), efficacy assays (including DA D1 or D2, or serotonin 5-HT2A receptors), CYP2D6 inhibition and QT-interval may be determined as described in PCT/DK04/000546, cf. in particular the “Example” section page 19-24 in the application text as filed for PCT/DK04/000546.
Further, the inventors have found that Compound I did not induce dystonia when tested in pigs sensitized to haloperidol, indicating that Compound I does not possess EPS (extrapyramidal symptoms) response/liability in humans.
PCT/DK04/000546 describes the following medical uses of Compound I: a disease in the central nervous system, including psychosis, in particular schizophrenia (e.g. positive, negative, and/or depressive symptoms) or other diseases involving psychotic symptoms, such as, e.g., Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, Delusional Disorder, Brief Psychotic Disorder, Shared Psychotic Disorder as well other psychotic disorders or diseases that present with psychotic symptoms, e.g. mania in bipolar disorder. Also described is the use of Compound I for treatment of anxiety disorders, affective disorders including depression, sleep disturbances, migraine, neuroleptic-induced parkinsonism, or cocaine abuse, nicotine abuse, alcohol abuse and other abuse disorders.
As indicated in PCT/DK04/000546 a group of compounds structurally related to Compound I, i.e. trans isomers of 3-aryl-1-(1-piperazinyl)indanes substituted in the 2- and/or 3-position of the piperazine ring, has been described in EP 638 073; Bøgesø et al. in J. Med. Chem., 1995, 38, 4380-4392 and Klaus P. Bøgesø in “Drug Hunting, the Medicinal Chemistry of 1-piperazino-3-phenylindans and Related Compounds”, 1998, ISBN 87-88085-10-4I. For example, an enantiomeric pure compound corresponding to formula (I) but differing in that it has an N-methyl group instead of an N-hydrogen on the piperazine has been disclosed in Bøgesø et al. in J. Med. Chem., 1995, 38, 4380-4392, see table 5, compound (−)-38.
None of the above references apart from PCT/DK04/000546 disclose the specific enantiomeric form above (Compound I) or medical use thereof. The trans isomer in the form of the racemate of Compound I is only indirectly disclosed as an intermediate in the synthesis of compound 38 in Bøgesø et al. in J. Med. Chem., 1995, 38, 4380-4392 while medical use of Compound I or its corresponding racemate is not described. Compound I as an intermediate is disclosed in PCT/DK04/000545 (WO05/016900).
Further details for the figures are revealed in the Examples below.